Pharmacology Flashcards
(168 cards)
1
Q
What is pharmacology?
A
The study of all compounds that interact with the body at all levels of organization. It includes the study of the therapeutic and adverse effects of these compounds.
2
Q
What is the difference between natural and synthetic compounds?
A
Natural: Produced by living organisms or derived from natural sources (plants, animals, microorganisms)
Synthetic: Artificially created in a laboratory through chemical reactions.
3
Q
What is the difference between endogenous and exogenous compounds?
A
Endogenous: Substances produced naturally within an organism or system.
Exogenous: Substances that originate outside of an organism or system and are introduced from an external source.
4
Q
Are pharmacology and pharmacy synonymous?
A
No. Pharmacy is a professional field that trains and qualifies individuals to prepare and dispense drugs.
5
Q
What are the 5 drug uses?
A
- Therapeutics
- Diagnosis
- Prophylaxis or prevention
- Veterinary medicine
- Horticulture (insect/parasite control)
6
Q
We use drugs in therapeutics to…
A
treat specific conditions
7
Q
Describe an example of drugs being used for diagnosis
A
Tuberculin purified protein derivative is used in a skin test to help diagnose TB infection.
8
Q
Name examples of drugs used for prophylaxis/prevention
A
Anti-histamines (e.g. to prevent seasonal allergies) or birth control (prevent pregnancy
9
Q
Many of the same drugs are used to treat both humans and …
A
animals
10
Q
Pesticides are …
What is the concern about pesticides?
A
Pesticides are drugs that are increasingly entering into human exposure (contaminated air, food, water).
11
Q
Drugs have three names…
A
- Chemical name (long, complex, of interest to chemists)
- Generic (nonproprietary) name (recognized internationally, usually only one)
- Proprietary, brand or trade name (patented exclusive property of the drug manufacturer; multiple for one drug)
12
Q
Give an example of a chemical, generic and proprietary name of a drug
A
Chemical: N-acetyl-para-aminophenol
Generic: Acetaminophen
Proprietary: Tylenol
13
Q
Pharmacokinetics
A
Studies the effect the organism has on the drug
14
Q
Pharmacodynamics
A
Studies the effect the drug has on the organism
15
Q
What are the 4 stages of pharmacokinetics? (ADME)
A
A: Administration
D: Distribution (how the drug moves through the body)
M: Metabolism (how the body metabolizes the drug)
E: Excretion (how the body removes the drug, if at all)
16
Q
What are the 3 features of drugs studied by pharmacodynamics?
A
- Drug effect
- Clinical efficacy
- Toxicity
17
Q
What is the difference between efficacy and potency of a drug?
A
Efficacy: Ability of the drug to produce the maximal desired response, regardless of the dose.
Potency: Amount of drug necessary to elicit a given response.
18
Q
Potency is often expressed as an…
A
EC50, or half-maximal effective concentration (indicates how much of a drug is needed to inhibit a biological process by half).
19
Q
Example of efficacious vs less efficacious drug
A
Opioid receptor agonists: morphine and codeine.
Desired response: Total pain relief
No dose of codeine can produce the same degree of pain relief as morphine, therefore morphine is a more efficacious drug.
20
Q
Which is considered more potent?
a) A drug that can relieve pain at a higher dose?
b) A drug that can relieve pain at a lower dose?
A
b) A drug that can relieve pain at a lower dose
21
Q
Is an efficacious drug necessarily potent?
A
No. An drug may be efficacious but not potent (can have a high maximum effect, but require a higher dose to achieve that effect than another drug). Conversely, a drug may be potent but not efficacious (can have significant effects at lower dose, but not necessarily the maximum possible effect).
22
Q
When choosing a drug, what is more important? Why?
a) efficacy
b) potency
A
a) efficacy
Efficacy is more important in determining whether a drug will be useful clinically, because if the drug does not produce the desired outcome, its potency is irrelevant.
23
Q
If two drugs have similar efficacies, which is often the most desirable?
a) the least potent drug
b) the most potent drug
A
b) the most potent drug
(you will have to take less of the drug to obtain the same effect)
24
Q
Define the therapeutic index (TI)
A
It is the margin of safety and the ratio between the dose of drug producing undesirable effects and the dose of drug producing the desired therapeutic effect.
25
Therapeutic index formula
TI = TD50/EC50
*TD50 = median toxic dose
26
Drugs with a large TI have a
a) large margin of safety
b) small margin of safety
a) large margin of safety
27
Why do drugs with a small TI need to be monitored in the plasma?
Because even small increases of the plasma levels could move the indiviual into the toxic zone
28
If toxic effects of a drug can start to occur at a dose only slightly higher than that needed for therapeutic effect, it has a...
a) large TI
b) small TI
b) small TI (small margin of safety)
29
When a drug has a large TI, we can monitor the ... and adjust the dose as needed. When a drug has a small TI, we monitor ... to readjust the dose as needed.
When a drug has a large TI, we can monitor the OUTCOME (e.g. sufficient decrease in blood pressure in a person suffering from hypertension).
When a drug has a large TI, or an effect that is difficult to monitor, we monitor PLASMA CONCENTRATIONS.
30
What are the 4 possible outcomes from drug treatment, given to different individuals with the same diagnosis and the same treatment?
1. Clinical benefit, no toxicity
2. Clinical benefit, toxicity
3. No clinical benefit, no toxicity
4. No clinical benefit, toxicity
(*4 is the least desirable outcome - if we're going to tolerate some toxicity, it is only if there is an important clinical outcome)
31
In what context is the outcome "clinical benefit, toxicity" often expected?
In oncology during cancer treatment. Cancer drugs often target rapidly dividing cells, which can include both cancerous cells and normal, healthy cells
32
Do drugs always work?
No! A lot of drugs have high rates of poor responses (e.g. beta-agonists for asthma have a poor response rate of 40-75%)
33
Why do drugs not always work?
Due to inter-patient variability! There is a plethora of different factors that may influence the effect of a drug on a given individual (environment, exercise, nutrition, smoking, metabolism, etc.)
34
Name 4 important factors contributing to inter-patient variability in drug responses
1. Age
2. Pregnancy
3. Menopause
4. Altered hormone status
35
PK, PD and drug responses differ between infants, adults and older adults largely due to...
normal physiologic changes associated with these periods of life (explains why same diagnosis and same treatment may lead to different outcomes).
36
Age affecting drug response: How does total body water change with age
It decreases with age (highest for infants, lowest for older adults)
37
Age affecting drug response: How does the percentage of lipophilic drugs retained in fatty tissue change with age?
The percentage of lipophilic drugs retained in fatty tissue increases with age (highest in older adults).
38
Age affecting drug response: How does liver metabolism change with age?
Liver metabolism peaks during adulthood, and decreases back down in older adulthood.
39
Age affecting drug response: How does renal clearance change with age?
Renal clearance peaks during adulthood, and decreases back down in older adulthood.
40
With age, there is also an increase in ... which may affect drug response.
comorbidities
41
Name 3 examples of socioeconomic factors that can contribute to variability in drug responses
1. Inadequate nutrition
2. Polypharmacy (how many drugs you're on)
3. Non-compliance
42
Pharmacogenetics
Area of pharmacology concerned with how genetic differences among individuals may affect both the therapeutic and adverse effects of drugs. Explains why the same diagnosis and same treatment can lead to different outcomes.
43
In pharmacogenetics, what are the two relevant genomes we must consider? What does each help determine?
1. The patient’s genome (germline): drug exposure and toxicity
2. The tumour genome (somatic): prognosis and effectiveness of targeted therapy
44
Cancer pharmacogenetics represent the standard of care in several cancer types, including… (3)
Breast cancer, non-small cell lung cancer, melanoma
45
Define cancer pharmacogenetics
Study of response to cancer drug treatment based on genetic biomarkers. It is a type of precision medicine.
46
Define compliance to treatment (in the context of pharmacology)
Patient’s adherence to the prescribed drug dosage regimen (extent to which a patient follows treatment instructions)
47
Therapeutic success of a drug depends on the patient’s… to the prescribed dosage regimen.
compliance
48
Describe the 4 types of non-compliance leading to poorer outcomes
1. The patient fails to obtain the medication
2. The patient fails to take the medication as prescribed
3. The patient prematurely discontinues the medication
4. The patient (or another person) takes the medication inappropriately
49
Most patients prefer … drugs to … drugs.
a) oral
b) injectable
Most patients prefer ORAL drugs to INJECTABLE drugs.
50
What is a major reason for therapeutic failure, especially in the long-term treatment, in pharmacology?
Non-compliance with the prescribed dosing schedule
51
Which is more common?
a) missed doses
b) too many doses
a) missed doses
52
Which do patients struggle with more?
a) remembering the number of drugs that they must take
b) remembering the number of doses of a drug per day/week that they must take
b) remembering the number of doses per day/week that they must take
53
Name one strategy to improve compliance to a drug treatment
Reducing the number of required dosing occasions
54
Why do patients fail to take their medication? (6)
1. Denial regarding sickness or drug efficacy
2. Forgetfulness (and other factors)
3. Stubbornness
4. Embarrassment
5. Route of exposure (it is easier to take oral drugs vs intravenous or intramuscular)
6. Intolerable side effects or interactions with other drugs
55
What are the 4 steps of the drug discovery process?
1. Research and development
2. Preclinical studies
3. Clinical trials
4. Review and approval
56
Explain the term "basket trial" (definition, focus, purpose)
- A basket trial tests one type of treatment across multiple cancer types.
- Focus: Patients with different cancer types but who share a common molecular or genetic alteration
- Purpose: To assess whether a specific treatment can be used across different cancer types that share the same genetic profile
57
What is the advantage of a basket trial?
The trial is not limited by the patients' diagnosis, but by the presence of a specific drug target
58
Explain the term "umbrella trial" (definition, focus, purpose)
- An umbrella trial tests multiple treatments within a single type of cancer
- Focus: Different subgroups within the same type of cancer classified by different molecular or genetic markers
- Purpose: Determine the best therapy (drug) for different genetic mutations within a single cancer type
59
Cytochrome P450s are a large family of ... that play a crucial role in...
Cytochrome P450s are a large family of ENZYMES that play a crucial role in the METABOLISM OF DRUGS.
60
Cytochrome P450s are mainly found in the ...
liver
61
Family of enzymes responsible for 50% of the elimination of common clinical drugs
Cytochrome P450s (CYPs)
62
CYP enzymes exhibit genetic polymorphisms. Why is this important?
This means individuals will have different versions (alleles) of these enzymes, which will affect how quickly or slowly they metabolize certain drugs. This can influence drug efficacy and risk of side effects.
63
Define a "prodrug"
A prodrug is an inactive or less active form of a drug that must be metabolized within the body to produce an active compound.
64
What are the two possible outcomes of a drug being metabolized by the body?
1. The prodrug is converted to its active form
2. A drug is converted to its inactive form
65
Take SSRIs (antidepressants) as an example. SSRIs are active drugs that are inactivated by the enzymes CYP2D6. How may an ultra-rapid metabolizer process the drug and what is the solution?
An ultra-rapid metabolizer will metabolize the drug too quickly, so the SSRI will rapidly inactivate.
Solution: Increase dose (if TI allows) or switch to a different drug.
66
Take SSRIs (antidepressants) as an example. SSRIs are active drugs that are inactivated by the enzymes CYP2D6. How may a slow metabolizer process the drug and what is the solution?
The drug will be metabolized slowly and circulate in the body in its active form for a longer time. This could potentially lead to toxicity.
Solution: Decrease dose.
67
Pharmacodynamics
Study of the effects of drugs on the body
68
Drugs are ligands for …
Receptors
69
Receptors are at the top of signaling pathways. Name two of their main roles.
1. Recognize a transmitter or hormone
2. Trigger a cellular response
70
Endogenous ligand (name two types)
Compound naturally produced by the body which binds and activates a receptor (neurotransmitter or hormone).
71
Agonist
A compound that mimics actions of the endogenous ligand
72
Antagonist
A compound that counters the actions of an agonist (blocks or opposes natural action or response of a receptor).
73
When trying to bind to a receptor, what do drugs compete with to exert their effects on cells?
Endogenous ligands
74
Other than neurotransmitter and hormone receptors, what are some other drug targets? (7)
1. Transporters
2. Enzymes
3. Voltage-gated ion channels
4. Structural proteins
5. DNA
6. RNA
7. Bacterial and viral enzymes
75
What is the most common type of receptor targeted by drugs?
G-protein coupled receptor (GPCR)
76
Name 3 types of common compounds that target GPCRs
Antihistamines
Caffeine
Opiates
77
What are the most common therapeutic actions of drugs acting on GPCRs? (2)
Antihypertensive, anti-allergic
78
Not all drugs act on “receptors”. NSAIDS target enzymes called…
cyclo-oxygenases
79
Not all drugs act on “receptors”. Local anaesthetics target…
Voltage-gated ion channels
80
Not all drugs act on “receptors”. L-DOPA, a drug used in Parkinson’s disease treatment, acts on…
precursor synthesis
81
Not all drugs act on “receptors”. Prozac (fluoxetine) targets…
5-HT transporter
82
Receptor-mediated actions tend to be…(4)
1. Of high potency/affinity
2. Tissue-selective
3. Chemically-specific
4. Inhibited by specific antagonists (assuming drug is an agonist)
83
What does it mean for a receptor-mediated action to be of high potency/affinity?
The receptor is activated at low drug concentrations (nanomolar to micromolar).
84
The difference in the chemical structure of adrenaline and noradrenaline is one methyl group. However, they have very different receptor-binding preferences. This is an example of...
Chemical specificity
85
Define the following:
[D], [R], [DR], k1, k2
[D]: concentration of drug
[R]: concentration of free receptors
[DR]: concentration of drug-receptor complex
k1: forward rate constant (rate at which drug binds receptor)
k2: reverse rate constant (rate at which drug-receptor complex dissociates)
86
The dissociation constant (KD) reflects the ...
binding affinity of a drug for its receptor
87
Low KD implies...
a) low affinity
b) high affinity
Explain your answer
b) high affinity
(because you can get 50% occupancy of the receptor at a low concentration)
88
KD is the concentration of drug at which...
50% of the receptors are occupied
89
At equilibrium, KD is equal to...
KD = k2/k1 = ([D][R])/[DR]
90
If there are no spare receptors, KD is equal to...
the EC50 (50% receptor occupancy produces half-maximal effect)
91
Receptor occupancy - definition and formula
Receptor occupancy describes the proportion of occupied receptors.
p = [D]/([D]+KD)
92
Receptor occupancy is independent of... and entirely dependent on...
Independent of: the concentration of free receptors
Dependent on: concentration of the drug and the drug's dissociation constant
93
What are the two assumptions we make when relating drug concentration to drug effect?
1. There is a linear relationship between the number of occupied receptors and drug effect
2. Only one agonist molecule at a time can bind one receptor.
94
When relating drug concentration to drug effect, we make 2 simple assumptions. If these assumptions are true, then...
Effect = ? x ?
Effect = max effect x proportion occupied
Effect = max effect x ([D]/([D]+KD))
95
Explain the concept of spare receptors
The maximal effect of an agonist can be achieved in a situation where less than 100% of the receptors are occupied.
96
How do occupancy and effect curves compare in a situation with no spare receptors (KD = EC50)
Both curves are identical
97
If 50% of the receptors are spare, how does the effect curve compare to the occupancy curve?
The maximum effect is achieved at only 50% occupancy. Therefore, the effect curve reaches a maximum 2x faster than the occupancy curve (it reaches a maximum BEFORE the occupancy curve). KD is NOT equal to EC50.
98
What is the efficacy of a full agonist, partial agonist and antagonist?
Full agonist: high efficacy
Partial agonist: medium efficacy
Antagonist: zero efficacy
*make sure you review the graphs in your slides
99
How does the binding affinity of a partial agonist compare to that of a full agonist?
A partial agonist will have the same binding affinity as a full agonist! However, it will have a decreased ability to produce the same degree of downstream effect.
100
How do partial agonists impact full agonists? Explain.
Partial agonists antagonize full agonists, because they can bind to the same receptor with the same affinity, but produce a weaker response.
101
When full and partial agonists compete for receptors, how is the overall response of the system affected?
The overall response of the system is reduced, as fewer receptors are available for the full agonist to elicit its maximum response.
102
1. In the absence of a full agonist, a partial agonist acts as an...
a) agonist
b) antagonist
2. In the presence of a full agonist, a partial agonist acts as an
a) agonist
b) antagonist
1. a) agonist (can still produce a response, though weaker than full agonist)
2. b) antagonist (reduces the possible max response by competing for receptors with the full agonist)
103
Buprenorphine is an example of a...
partial agonist for the mu-opioid receptor
104
Name 3 key facts about buprenorphine (other than that it is a partial agonist)
1. It is a safer analgesic than heroin (heroin = full agonist)
2. It can blunt the heroin high
3. It can trigger withdrawal
105
Define constitutive receptor activity (aka basal activity)
Intrinsic activity of a receptor in the absence of a ligand.
106
What is the efficacy of an inverse agonist?
Negative efficacy
* make sure to review the graph in your slides!
107
Define the concept of inverse agonist. How does it differ from an antagonist?
Inverse agonist: Binds the same receptor as an agonist, but produces the opposite effect. It reduces the receptor's activity below its basal level.
Antagonist: Binds to the receptor but does not produce an effect on its own. It simply blocks or prevents the action of an agonist!
108
Explain how reverse agonists can be clinically useful?
Many diseases are characterized by genetic mutations that cause increased basal activity of receptors. Inverse agonists can then be used to reverse this excess activity.
109
Surmountable antagonism reflects...
competitive reversible antagonism
110
Describe surmountable antagonism and summarize its 3 key characteristics
Effects of an antagonist can be overcome by increasing the concentration of an agonist.
1. Reversible binding (antagonist can dissociate allowing agonist to bind instead)
2. Shift in dose-response curve to the right (the greater the antagonist concentration, the greater the agonist concentration needed to achieve the max effect)
3. No change in max response (efficacy)
*EC50 increase
111
Insurmountable antagonism reflects either ... or ...
competitive irreversible antagonism or noncompetitive antagonism
112
Describe competitive irreversible antagonism
Antagonist makes a permanent or near-permanent bond with the receptor - cannot be displaced by increasing the concentration of the agonist.
Efficacy is decreased because the maximum effect can no longer be achieved. EC50 will increase (a higher dose will be required to achieve the half maximal effect).
113
Describe noncompetitive antagonism
The antagonist binds to a site on the receptor other than the active site (i.e. it binds an allosteric site). Since they are not competing for the same binding site, increasing agonist concentration will not influence antagonist binding. This results in decreased efficacy as [antagonist] is increased. EC50 will increase.
114
Noncompetitive antagonism is an example of...
allosteric modulation (particle affecting receptor activity by binding to a site other than the ligand-binding site)
115
Some allosteric modulators can increase the effects of an agonist. How is the efficacy impacted?
The allosteric modulators could increase the maximum effect exerted by an agonist, therefore increasing its efficacy.
116
Toxicology
Science of adverse effects of substances on biological and ecological systems
117
Toxicant
Any substance that is harmful to a living organism
118
Difference between toxicant and toxin
Toxins: produced by biological organisms
Toxicants: synthetic, human-made txic chemicals
119
What differentiates a poison from a remedy?
Dose (Paracelsus)
120
Difference between pharmacology and toxicology
Pharmacology: studies drugs in order to produce desired effects
Toxicology: studies chemicals to identify whether they produce undesired effects, actions of poisons (non-therapeutic), effects of environmental chemicals on human health
121
Natural substances do NOT necessarily mean safe substances! Name some examples
Star of Bethlehem Oak - blocks channels, can cause cardiac arrest
Belladona - dilates pupils
Poison Ivy - skin irritation
Yew - used to make taxol (anti-cancer drug)
Natural substances can be very toxic or make powerful drugs.
122
Adverse effects of drugs may be... (2)
1. Dose-related (extension of the desired or therapeutic effect)
2. Surprise toxicity (unrelated to the therapeutic effect i.e. side effect)
123
DDT is an organochlorine insecticide. Explain its mechanism of action.
DDT blocks sodium channels in the nervous system and disrupts the propagation of action potentials. It causes uncontrolled repetitive spontaneous discharges along the nerve.
124
What were the advantages and disatvantages of DDT?
Advantages: great insecticide, killed millions of mosquitoes and reduced malaria rates significantly
Disadvantages: immense environmental impact + cancer
125
DDT was banned in the US in 1972. Why is it still being used in Mexico?
Because a decrease in use of DDT is strongly correlated with an increase in cases of malaria
126
Toxicology also looks at ADME. Define this acronym and explain how it differs from the pharmacological approach.
A: Administration
D: Distribution
M: Metabolism
E: Excretion
In toxicology, the difference is in administration, which is more limited than that of drugs (we cannot ethically inject a toxicant).
Administration is limited to:
- skin (dermal)
- inhalation
- ingestion
127
What is the purpose of toxicity testing?
To characterize the toxicity profiles of chemicals (or biologicals).
128
All drugs developed for human use are tested in 2 disciplines...
1. Safety pharmacology
2. Preclinical toxicology
129
What are the different phases of "safety" pharmacology in drug development?
1. Early drug discovery
2. Nonclinical studies (to enable first-in-human testing - FIH)
3. Clinical trials (3 phases)
4. Launch of new drug
*Toxicology is involved in ALL of these phases*
130
During drug development, close to 30,000 early drugs are narrowed down ton only one clinical drug product. What is one of the main reasons for elimination of potential drugs in this process?
Toxicology assessments show that the drugs have toxic, adverse effects.
131
What is the ICH?
International Council for Harmonisation of technical requirements for pharmaceuticals for human use
132
What is the role of the ICH?
Standardize and harmonize international scientific and technical guidelines for pharmaceutical DRUG development and registration.
This means DRUGS are highly regulated before being made accessible to humans.
133
We are exposed to chemicals in... (3)
1. The workplace
2. Consumer products
3. Our environment
134
What is the most important risk factor for global deaths by pollution?
Air pollution causes the highest number of estimated global deaths
135
There are 80 million synthetic substances, 140,00 of which are chemicals used in commerce. What percentage of these chemicals is tested?
Less than 10%
136
What is the OECD?
Organisation for Economic Co-operation and Development
137
What is the role of the OECD?
Organisation promoting policies for improving global health, safety and well-being, including policies for chemical testing. It is responsible for determining the safety levels for chemicals used in manufacture.
138
Name examples of OECD guideline tests.
- Skin sensitization
- Dermal toxicity
- Ocular toxicity
- Inhalation toxicity
- Oral toxicity
- Neurotoxicity
- Immunotoxicity
- Cytotoxicity
- Developmental toxicity
- Reproductive toxicity
- Genotoxicity
139
The OECD uses a ... strategy to test the effects of chemicals on health.
Tiered testing strategy
140
Describe the tiered testing strategy
It is a stepwise approach for testing used to evaluate the safety and toxicity of chemicals.
Tier 1:
Tier 2:
Tier 3:
Tier 4:
Tier 5:
141
Animal studies are often used for estimating human toxicity. However, there is a level of uncertainty when applying what we learn from animals to humans. Why is that?
Most toxicology studies are done on rats, which tend to be extremely similar to each other (similar weight, similar ages, similar health).
Humans are not so uniform (there are enormous fluctuations in height, weight, age, health status, obesity, etc.)
142
What are some modifiers of toxicity that create uncertainty in a given individual's response to a potential toxicant?
- Exposure (route, site)
- Genetic polymorphisms
- Nutritional status (e.g. obesity)
- Presence of other drugs or chemicals
143
What is the CEPA?
Canadian Environmental Protection Act
144
Based on the CEPA, substances are deemed to be toxic if they enter, or may enter, the environment in amounts that... (3)
1. have an immediate or long-term effect on the environment or its biological diversity
2. Endanger the environment upon which life depends
3. Endanger human life or health
145
To assess whether a chemical should be banned, we must determine the ..., ... and ... of exposure that is experience or anticipated.
We must determine the type, level and duration.
146
4 mechanisms for hazard identification
- structure-activity analysis
- in vitro tests
- animal bioassays
- epidemiology
147
Formula for risk assessment
Risk = exposure * hazard
148
Risk occurs when exposure concentrations exceed those at which...
toxic effects are observed
149
What is an endocrine disrupting chemical (EDC)?
An EDC is an exogenous substance that alters functions of the endocrine system and consequently causes adverse health effects.
*EDCs are everywhere in our everyday environment!
150
What are some of the reported health impacts of EDCs (6)?
1. Obesity
2. Female fertility
3. Embryo development
4. Thyroid
5. Male fertility
6. Brain functions
151
In toxicology, we do not always see simple dose-response curves. Explain the difference between monotonic and non-monotonic dose-response relationships
Monotonic: Effect of a substance consistently increases (or decreases) with increasing dose (linear or sigmoidal relationship)
Non-monotonic: Effect of a substance does not follow a single, predictable pattern as dose increases (u-shaped, inverted u-shaped, multi-phasic).
152
Exposure to EDCs may have long-lasting consequences, sometimes even ... effects
transgenerational effects (if a chemical is toxic to germ cells)
153
International laws do not contain specific provisions for EDCs. What else poses a problem for the coherent identification and risk management of EDCs?
Absence of an EDC hazard class in Classification Labelling and Packaging (CLP) Regulation and/or the Globally Harmonized System of Classification and Labelling of Chemicals.
154
Why do we have poison centres?
In Canada, 1,500 people lose their lives and 8,000 are hospitalized due to unintentional poisoning from common substances in our homes
155
More than 1/3 of the Poison Centre cases involve a ...
child aged 5 or less
156
What do you do when you see a poisoned patient?
1. Maintain vital signs
2. Identify the poison
3. Decontaminate
4. Enhance elimination of the poison
5. Administer antidote (note that antidotes rarely exist for most poisons)
157
Name 3 examples of poison antidotes
- antivenom
- chelating agents
- receptor antagonists (Naloxone)
158
In pharmacology, we design specific drugs to target a specific receptor to produce a specific effect. In contrast, in toxicology chemicals can act on ... in ... and can have ...
In toxicology, chemicals can act on multiple receptors in multiple tissues and can have multiple effects (we do not control their effects by design).
159
Most toxicants have...
a) irreversible interactions with target receptors
b) reversible interactions with target receptors
Explain why.
b) reversible interactions with target receptors
Because unlike drugs, they are not designed to be high-affinity binders.
160
LOAEL
Lowest Observed Adverse Effect Level: lowest dose at which adverse effects are first observed
161
NOAEL
No Observed Adverse Effect Level: highest dose at which no harmful effects are observed
162
Threshold
Concentration at which any effects of a chemical are observed (usually not yet adverse effects)
163
Why is there a threshold to observe any effects of a chemical?
Our bodies have the ability to neutralize "nasty" chemicals to some degree (e.g. cytochrome P450 enzymes in the liver). Thus up to a given THRESHOLD, you can administer a drug/chemical without producing an effect.
164
During the drug development process, more expensive and lengthy tests (e.g. cancerogenicity) are carried out ... in the drug development process.
a) sooner
b) later
b) later
(to avoid wasting effort and money testing drugs, most of which are eliminated upstream because of toxicity)
165
Describe the tiered testing strategy
Aimed at making chemical testing quicker and more cost-effective.
Tier 1: In silico, computer-based analyses (comparing chemical structure to known compounds)
Tier 2: In vivo and in vitro screens
Tier 3: In vitro whole cell activity assessment
Tier 4: Fish and amphibian whole animal assessment
Tier 5: Mammalian whole animal assessment
We only move on to the next tier if we find that the chemical is not likely to be toxic.
166
To account for the uncertainty of moving from animal tests to human conclusion, the NOAEL is decreased by a factor of... and then to account for human variability, it is decreased by another order of ...
10
167
How do we determine risk?
By determining the level of exposure to a chemical and determining the specific hazard (what chemical is posing the risk).
168
Risk occurs when...
exposure concentrations exceed those at which toxic effects are observed.
